About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

December 14, 2012

Mipomersen In Trouble

Posted by Derek

I wrote here in 2009 about Kynamro (mipomersen), an antisense oligonucleotide from Isis targeted LDL cholesterol levels. At the time, Isis and Genzyme were starting to look at its use in people with familial hypercholesterolaemia, and its prospects looked promising to become at least a profitable niche drug.

But the European Medicines Authority just turned down the drug, saying that its risk/benefit ratio just looks unacceptable. Efficacy was not in doubt, but a substantial number of patients stopped taking mipomersen because of side effects, including liver toxicity. That's bad enough, but the treatment groups also showed a great incidence of cardiovascular events, which is particularly worth thinking about when you're trying to lower LDL to prevent. . .cardiovascular events.

Human lipid handling continues to be a minefield for new therapies. The statins (which lower LDL through inhibiting cholesterol biosynthesis) appear, more and more, to be outliers in their safety and efficacy. That's not to say that statin drugs never have problems (they do - just ask Bayer, among others). But the risk/benefit for them does appear to be robust and positive, and how many other lipid-altering drugs can say that?

Everyone new report just further cements my belief that Cholesterol numbers are just a biomarker for CV health and the thinking that Statin's HMG-CoA inhibition is it's clinically relavent MOA has lead many astray

The FDA Advisory panel recommended it for approval, albeit on a close vote, but definitely thought better of it than the EMA.
As one panel member said: “We need a toolkit, we need as many options as possible for these patients,” It's a shame the EMA feels otherwise.

I would argue that the human genetic evidence is pretty impressive for LDL lowering by any means. The issues with mipomersen are likely due to the RNA modality, but the PCSK9 monoclonals will be a much better test. HDL raising is a different beast with far less human genetics support and I will be very curious how those pharmacological interventions work out.